The macrolide antibiotics are a large class of compounds, many derived from Streptomyces spp, which comprise a saturated C13ONx (where x is 0 or 1) macrocyclic lactone ring substituted by one or more sugars, generally at the 5-carbon and optionally also at the 3-carbon. One early example is erythromycin A which has a C13O ring substituted by sugars at the 3 and 5 ring carbons (the ester carbonyl is at the 1 position and the ester ring oxygen at the 14 position).
Later generation macrolide antibiotics include clarithromycin (which is methoxy substituted at the 6-carbon), azithromycin (which has a ring nitrogen between the 9- and 10-carbons, i.e. at the 9a position), telithromycin (which is oxo-substituted at the 3-carbon, methoxy-substituted at the 6-carbon, and has the 11- and 12-carbons substituted by a bridging N-(4-(pyridin-3-yl)-imidazol-1-yl-butyl)cyclic carbamate group), roxithromycin (which is substituted at the 9 position an O-alkylated oxime group), dirithromycin (which is substituted at the 9 and 11 positions by a substituted oxazine group), flurithromycin (which is 8-substituted by fluorine), CP 544372 (which is substituted on the 4′ position of the 3-attached sugar by a 2-methoxyphenyleth-1-yl-N-ethyl-aminoethyl-aminocarbonyloxy group and at the 9 position by an amino group), and cethromycin (which is substituted at the 3 position by an oxo group, at the 6 position by a quinolin-3-yl allyloxy group and at the 11 and 12 positions by a cyclic urethane group). Further known antibiotic macrolides include A20316, A69334, A66321, A60565, A216599, A217213, A229339, A241550, CP642959, CP654743, CP642957, CP647762, CP647763, FMA122, FMA174, FMA187, FMA199, FMA367, FMA481, HMR3004, HMR3562, HMR3787, L701677, RWJ415663, RWJ415667, TE604, TE802, TE810, TEA777 and TEA824. Other examples may be found in Asaka et al. Current Topics in Medicinal Chemistry 3: 961-989 (2003) and Wu et al Current Medicinal Chemistry 8: 1727-1758 (2001) and the references therein the contents of all of which are hereby incorporated herein by reference.
The 3-oxo-substituted macrolides are also referred to as ketolides.
A further general feature of the known macrolides is that the 5-sugar is 3′-substituted by a secondary nitrogen (e.g. by a —N(CH3)2 group), that the 6-carbon carries a hydroxy or substituted hydroxy group, and that they are methyl-substituted at the 2, 4, 6, 8, 10 and 12-carbons.
As with antibiotics in general, there is an ongoing need for novel macrolide antibiotics as drug resistance to the existing compounds appear. There is also a need to increase the activity profile, i.e. the antibacterial toxicity and the range of bacteria against which the macrolide antibiotics are toxic.
While modifying the ring substitution of the macrolides at many ring positions, in particular at the 3, 5, 6, 8, 9, 11 and 12 carbons and between the 9- and 11-carbons and between the 11- and 12-carbons, has been widely suggested, in the over 50 years since the development of erythromycin it has not to our knowledge been suggested that useful new macrolide antibiotics can be produced by modifying the substitution of the 10-carbon. Methyl substitution at the 10-carbon appears to have been uniformly considered to be essential. This is nicely illustrated by Chiron's recent PCT application WO 03/004509 which shows optional substitutional modification at the 2, 4, 6, 9, 11, 12 and 13 carbons (and remember the known macrolide flurithromycin has substitutional modification at the 8-carbon) but still mandates retention of the methyl groups at the 2, 4, 6, 8 and 10 carbons.